Vledulloblastoma is among the most common and significant cancers in children. Treatment of this disease s still suboptimal in the sense that long-term survival is only about 50%. Current therapeutic strategies are often associated with significant long-term morbidity, which are frequently devastating to patients. Therefore, novel, non-toxic therapeutic approaches are needed. The concept of modulating a key signal transduction pathway in this tumor type is appealing from a therapeutic point of view. The sonic hedgehog (Shh) signaling pathway is one clear molecular basis for this tumor type, and most investigators believe that a better understanding of the control of this pathway may provide insight into novel therapeutic targets. Our preliminary data show that the peptide PACAP (pituitary adenylyl cyclase activating peptide) regulates the Shh signaling pathway and inhibits proliferation in cerebellar granule cells, the cells that give rise to medullobastomas. Furthermore, mice heterozygous for deletion of the PACAP gene are more sensitive to the generation of medulloblastomas than patched-1 heterozygotes (Ptc+/'), as Ptd^'PACAP*''double heterozygous (DH) mice have a medulloblastoma incidence of 66% (compared to only 15% in Ptc+/~ mice). Our hypothesis is that PACAP is a small molecular inhibitor of the Shh pathway and can kill medulloblastoma cells more effectively and selectively than standard chemotherapy agents. In this current proposal, we will expand upon previous studies of PACAP in a more translational direction, with the broad, long-term objectives of developing novel therapies that are specifically targeted against growth control pathways altered in medulloblastoma. The goals of the specific research proposed herein are to investigate the role and mechanism of PACAP as a regulator of Shh-driven tumor progression/growth and to test the potential application of PACAP peptide as a novel therapeutic strategy for the treatment of medulloblastoma. To achieve this goal, we will use our new Ptd^'PACAP*''medulloblastoma mouse model and primary human medulloblastoma tissues/cells and xenograftsfor the following specific aims: 1) to investigate the anti-tumor effects and mechanism of PACAP peptide in our double heterozygous Ptd*''PACAP*''mouse model of medulloblatoma in vitro and in vivo;and 2) to determine the role and mechanism of PACAP in human medulloblastomas in vitro and in vivo. The rationale for performing complementary in vitro and in vivo translational studies in both a mouse model and human tumors is to allow for a more comprehensive and rigorous pre-clinical assessment of PACAP function and anti-tumor efficacy. The information generated from this research will be of significant direct relevance to public health, as this may potentially lead to the development of a novel therapeutic strategy for patients with medulloblastomas.